The conformation of a drug molecule is initimately related to its function. This research will identify potential constraints on drug conformation in the experimental antitumor agents tiazofurin and selenazofurin. Tiazofurin (TF) and selenazofurin (SF) are new C-glycosyl nucleosides currently undergoing clinical trials. In vivo, TF and SF are incorporated into analogues of the cofactor NAD. These NAD analogues act as inhibitors of inosine monophosphate dehydrogenase, the putative cause of cytotoxicity. Crystal structures of TF and SF show unusual close contacts between the heteroatom in the base (S or Se) and the furanose ring oxygen, suggesting that the conformations of these agents and/or their NAD analogues may be restricted in solution. This would have important implications for drug binding and activity. Computational results suggest that the heteroatom-oxygen interaction is in part electrostatic. Thus, the correlation between heterocycle charge and glycosyl bond conformation will be examined in a series of new base-substituted analogues of tiazo- and selenazofurin. Crystallographic, computational and NMR techniques will be employed. A crystallographic data base survey of compounds showing close intramolecular contracts will be performed in order to further identify the origins of the heteroatom-oxygen interaction. NMR experiments employing a variety of proton and heteronuclear techniques will examine the conformation of the parent compounds and the NAD analogues in solution. Enzyme inhibition and modeling studies will investigate binding of the NAD analogues to other dehydrogenases and correlate binding ability with changes in glycosyl bond conformation.